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Aging and disease    2019, Vol. 10 Issue (5) : 992-1002     DOI: 10.14336/AD.2018.0926
Orginal Article |
Role of Regulatory T cells in Atorvastatin Induced Absorption of Chronic Subdural Hematoma in Rats
Wei Quan1,2, Zhifei Zhang1,2,3, Pan Li4, Qilong Tian5, Jinhao Huang1,2, Yu Qian1,2, Chuang Gao1,2, Wanqiang Su6, Zengguang Wang1,2, Jianning Zhang1,2, Alex Zacharek7, Poornima Venkat7, Jieli Chen7,*, Rongcai Jiang1,*
1Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin, China.
2Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Tianjin, China.
3Department of Neurosurgery, The First Central Hospital of Tianjin, Tianjin, China.
4Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China.
5Department of Neurology, Tangdu Hospital, Baqiao, Shanxi, China.
6Department of Neurosurgery, The First Central Hospital of Baoding City, Lianchi, Baoding, China.
7Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
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Abstract  

Chronic subdural hematoma (CSDH) is a neurological disorder with a substantial recurrence rate. Atorvastatin is an effective drug for treating hyperlipidemia and known to improve neurological outcome after intracerebral hemorrhage. Previous studies have reported that atorvastatin treatment promotes hematoma absorption in CSDH, while the underlying mechanisms remain unclear. In this study, we investigated whether the anti-inflammatory effects of atorvastatin mediate absorption of CSDH. 144 male, Wistar rats (6 months old) were randomly divided into the following groups: 1) sham surgery control, 2) treatment: CSDH + atorvastatin, and 3) vehicle control: CSDH + saline. Atorvastatin or saline was orally administered daily for 19 days after CSDH procedure. A T2WI MRI was used to evaluate CSDH volume changes during the time course of the study. Flow cytometry and immunohistochemical staining were used to measure the number of regulatory T cells (Treg). ELISA was used to measure cytokine level in the hematoma border. Neurological function and cognitive outcome were evaluated using Foot-Fault test and Morris Water Maze test, respectively. When compared to saline treatment, atorvastatin treatment accelerated the absorption of CSDH as indicated by decreased hematoma volume in T2WI MRI data on 14th and 21st day after CSDH (P<0.05). Atorvastatin treatment significantly increased the number of Treg in circulation and hematoma border from 3rd to 21st day after CSDH. Atorvastatin treatment significantly decreased the levels of interleukins (IL-6 and IL-8) and tumor necrosis factor-α (TNF-α), but increased IL-10 level in the hematoma border. Atorvastatin treatment also improved neurological function and cognitive outcome compared to vehicle treated group. Atorvastatin induced anti-inflammatory responses and increased Treg in circulation and brain which may contribute to the accelerated CSDH absorption in rats.

Keywords chronic subdural hematoma      atorvastatin      inflammation      regulatory T cell      cytokines     
Corresponding Authors: Chen Jieli,Jiang Rongcai   
About author:

These authors contributed equally to this work.

Just Accepted Date: 16 November 2018   Issue Date: 27 September 2019
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Quan Wei
Zhang Zhifei
Li Pan
Tian Qilong
Huang Jinhao
Qian Yu
Gao Chuang
Su Wanqiang
Wang Zengguang
Zhang Jianning
Zacharek Alex
Venkat Poornima
Chen Jieli
Jiang Rongcai
Cite this article:   
Quan Wei,Zhang Zhifei,Li Pan, et al. Role of Regulatory T cells in Atorvastatin Induced Absorption of Chronic Subdural Hematoma in Rats[J]. Aging and disease, 2019, 10(5): 992-1002.
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http://www.aginganddisease.org/EN/10.14336/AD.2018.0926     OR     http://www.aginganddisease.org/EN/Y2019/V10/I5/992
Figure 1.  Measurement of hematoma volume at various time points after CSDH using MRI. T2WI sequence MRI scanning shows that atorvastatin treatment decreases hematoma volume from 14 to 21 days after CSDH. (A-C) Representative MRI images of the CSDH saline-treated rats and (D-F) CSDH-atorvastatin treated rats. (G) Hematoma volume quantitative data.
Figure 2.  Atorvastatin treatment increases Treg expression in brain tissue of CSDH rats. FoxP3 immunohistochemical staining was used to detect Treg expression in brain tissue. FoxP3+ cells are primarily detected in the vicinity of the intracranial hematoma lesions, and atorvastatin promotes its expression. The dura membrane and its hematoma on days 3, 14 and 21 after CSDH are represented in panels A-C for non-treated CSDH rats, and in panels D-F for atorvastatin treated CSDH rats with quantitative data presented in panel G.
Figure 3.  Atorvastatin treatment increases Treg expression in peripheral blood of CSDH rats as measured by flow cytometry. A) Representative dot plots showing the gating strategy. B) Representative dot plots of Treg cells in the sham control and CSDH-non-treated rats. Panel C) Representative dot plots of Treg cells in Atorvastatin treated rats. Quantitative data for Treg in peripheral blood is presented (D).
Figure 4.  Higher circulating Treg correlates with lower hematoma volume in CSDH rats. Linear correlation analysis indicates that lower hematoma volume after CSDH correlates with Treg increase in peripheral blood (r2= 0.448, P<0.05, panel A), and brain (r2= 0.727, P<0.05, panel B).
Figure 5.  Atorvastatin treatment increases IL-10, and decreases IL-6, IL-8, and TNF-α expression in brain tissue of CSDH rats. Atorvastatin treatment significantly decreases expression of (A) TNF-α, (B) IL-6 and (C) IL-8 while increasing (D) IL-10 expression in the dura and hematoma boundary tissue compared to saline-treated CSDH rats. #P<0.05 for CSDH saline treated group vs. sham control group; *P<0.05 for CSDH atorvastatin treated group vs. CSDH saline treated group.
Figure 6.  Atorvastatin treatment improves neurological and cognitive outcome in CSDH rats. A) CSDH induces significant neurological impairment compared to sham control rats, and Atorvastatin treatment improves neurological function as indicated by foot-fault test. B) CSDH induces significant cognitive impairment compared to sham control rats, and Atorvastatin treatment improves spatial learning and memory as indicated by Morris water maze test. #P<0.05, CSDH non-treated group vs. sham control group and *P<0.05, CSDH Atorvastatin treated group vs. CSDH-non-treated group.
[1] Szczygielski J, Gund SM, Schwerdtfeger K, Steudel WI, Oertel J (2016). Factors affecting outcome in treatment of chronic subdural hematoma among ICU patients: impact of anticoagulation. World Neurosurg, 92:426-433.
[2] Kamenova M, Lutz K, Schaedelin S, Fandino J, Mariani L, Soleman J (2016). Does early resumption of low-dose aspirin after evacuation of chronic subdural hematoma with burr-hole drainage lead to higher recurrence rates? Neurosurgery, 79:715-721.
[3] Schwarz F, Loos F, Dünisch P, Sakr Y, Safatli DA, Kalff R, et al. (2015). Risk factors for reoperation after initial burr hole trephination in chronic subdural hematomas. Clin Neurol Neurosurg, 138:66-71.
[4] Winn H (2017). Medical and surgical management of chronic subdural hematomas. In: AswinC, AngelosGK, NicholasB, PeterJH, ThomasS, editors. Youmans Neurological surgery. Amsterdam: Elsevier, 310-317.
[5] Leroy HA, Aboukaïs R, Reyns N, Bourgeois P, Labreuche J, Duhamel A, et al. (2015). Predictors of functional outcomes and recurrence of chronic subdural hematomas. J Clin Neurosci, 22:1895-1900.
[6] Osuka K, Watanabe Y, Usuda N, Aoyama M, Iwami K, Takeuchi M, et al. (2017). Inhibitory mechanism of the outer membrane growth of chronic subdural hematomas. J Neurotrauma, 34:1996-2000.
[7] Park KS, Park SH, Hwang SK, Kim C, Hwang JH (2015). Correlation of the Beta-trace protein and inflammatory cytokines with magnetic resonance imaging in chronic subdural hematomas: a prospective study. J Korean Neurosurg Soc, 57:235-241.
[8] Wang Y, Mao L, Zhang L, Zhang L, Yang M, Zhang Z, et al. (2016). Adoptive regulatory T-cell therapy attenuates subarachnoid hemorrhage-induced cerebral inflammation by suppressing TLR4/NF-B signaling pathway. Curr Neurovasc Res, 13:12112-12116.
[9] Yang Z, Yu A, Liu Y, Shen H, Lin C, Lin L, Wang S, Yuan B (2014). Regulatory T cells inhibit microglia activation and protect against inflammatory injury in intracerebral hemorrhage. Int Immunopharmacol, 22:522-525.
[10] Xu X, Gao WW, Cheng SQ, Yin DP, Li F, Wu YG, et al. (2018). Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J Neuroinflammation, 14:167.
[11] Chen JL, Zhang CL, Jiang H, Li Y, Zhang LJ, Robin A, et al. (2005). Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab, 25:281-290.
[12] Chen J, Zhang ZG, Li Y, Wang Y, Wang L, et al. (2003). Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol, 53:743-751.
[13] Francisco J, Félix R, Maria G, Daniel FB (2013). Cholesterol and cardiovascular disease in the elderly. Facts and Gaps. Aging Dis, 4:154-169.
[14] Rodríguez-Perea AL, Gutierrez-Vargas J, Cardona-Gómez GP, Guarin CJ, Rojas M, Hernández PA (2017). Atorvastatin modulates regulatory T cells and attenuates cerebral damage in a model of transient middle cerebral artery occlusion in rats. J Neuroimmune Pharmacol, 12:152-162.
[15] Rodríguez-Perea AL, Montoya CJ, Olek S, Chougnet CA, VelillaPA, (2015). Statins increase the frequency of circulating CD4+ FOXP3+ regulatory T cells in healthy individuals. J Immunol Res, 2015:762506.
[16] Li T, Wang D, Tian Y, Yu H, Wang Y, Quan W, et al. (2014). Effects of atorvastatin on the inflammation regulation and elimination of subdural hematoma in rats. J Neurol Sci 341:88-96.
[17] W Dong, Li T, Wei HJ, Wang Y, Yang GL, Tian Y, et al. (2016). Atorvastatin enhances angiogenesis to reduce subdural hematoma in a rat model. J Neurol Sci, 362:91-99.
[18] Jiang RC, Zhao SG, Wang RZ, Feng H, Zhang JM, Li XG, et al. (2018). Safety and efficacy of atorvastatin for chronic subdural hematoma in Chinese patients. JAMA Neurol, 75:1338-1346.
[19] Wang D, Li T, Tian Y, Wang S, Jin C, Wei H, et al. (2014). Effects of atorvastatin on chronic subdural hematoma: a preliminary report from three medical centers. J Neurol Sci, 336:237-242.
[20] Chan DY, Chan DT, Sun TF, Ng SC, Wong GK, Poon WS (2017). The use of atorvastatin for chronic subdural haematoma: a retrospective cohort comparison study. Br J Neurosurg, 31:72-77.
[21] Quan W, Zhang Z, Tian Q, Wen X, Yu P, Wang D, et al. (2015). A rat model of chronic subdural hematoma: Insight into mechanisms of revascularization and inflammation. Brain Res, 1625:84-96.
[22] Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T, et al. (2007). FOXP3+ regulatory T Cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res, 13:902-211.
[23] Geraldo R, Maria F, Fabiana A, Omar J, Sérgio C, Francine B, et al. (2018). Aging and end stage renal disease cause a decrease in absolute circulating lymphocyte counts with a shift to a memory profile and diverge in Treg population. Aging Dis, in press.
[24] Rabe H, Nordström I, Andersson K, Lundell AC, Rudin A (2014). Staphylococcus aureus convert neonatal conventional CD4(+) T cells into FOXP3(+) CD25(+) CD127 (low) T cells via the PD-1/PD-L1 axis. Immunology, 141:467-481.
[25] Zhang Y, Chopp M, Zhang ZG, Katakowski M, Xin H, Qu C, et al. (2017). Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int, 111:69-81.
[26] Morris R (1984). Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods, 11:47-60.
[27] Kalamatianos T, Stavrinou LC, Koutsarnakis C, Psachoulia C, Sakas DE, Stranjalis G (2013). PlGF and sVEGFR-1 in chronic subdural hematoma: implications for hematoma development. J Neurosurg, 118:353-357.
[28] Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, et al. (2004). HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke, 35:1744-1749.
[29] Karki K, Knight RA, Han Y, Yang D, Zhang J, Ledbetter KA, et al. (2009). Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke, 40:3384-3389.
[30] Jiang R, Wang D, Poon WS, Lu YC, Li XG, Zhao SG, et al. (2015). Effect of atorvastatin on chronic subdural hematoma (ATOCH): a study protocol for a randomized controlled trial. Trials, 18:528.
[31] Van der Veeken J, Gonzalez AJ, Cho H, Arvey A, Hemmers S, Leslie CS, et al. (2016). Memory of inflammation in regulatory T cells. Cell, 166:977-990.
[32] Xia JY, Wang HJ, Guo JF, Zhang ZJ, Coder B, Su DM (2012). Age-related disruption of steady-state thymic medulla provokes autoimmune phenotype via perturbing negative selection. Aging Dis, 3:248-259.
[33] MahmoudF, Al-OzairiE, (2013). Inflammatory cytokines and the risk of cardiovascular complications in type 2 diabetes. Dis Markers, 35:235-241.
[34] Eikawa S, Ohue Y, Kitaoka K, Aji T, Uenaka A, Oka M, et al. (2010). Enrichment of Foxp3+ CD4 regulatory T cells in migrated T cells to IL-6- and IL-8-expressing tumors through predominant induction of CXCR1 by IL-6. J Immunol, 185:6734-6740.
[35] Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007). CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci, 104:19446-19451.
[36] Arima Y, Harada M, Kamimura D, Park JH, Kawano F, Yull FE, et al. (2012). Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell, 148:447-457.
[37] Arnold SA, Hagg T (2011). Anti-inflammatory treatments during the chronic phase of spinal cord injury improve locomotor function in adult mice. J Neurotrauma, 28:1995-2002.
[38] Li XL, Li H, Zhang M, Xu H, Yue LT, Zhang XX, et al. (2016). Exosomes derived from atorvastatin-modified bone marrow dendritic cells ameliorate experimental autoimmune myasthenia gravis by up-regulated levels of IDO/Treg and partly dependent on FasL/Fas pathway. J Neuroinflammation, 13:1-18.
[39] Xu H, Li XL, Yue LT, Li H, Zhang M, Wang S, et al. (2014). Therapeutic potential of atorvastatin-modified dendritic cells in experimental autoimmune neuritis by decreased Th1/Th17 cytokines and up-regulated T regulatory cells and NKR-P1(+) cells. J Neuroimmunol, 269:28-37.
[40] Yang D, Knight RA, Han Y, Karki K, Zhang J, Ding C, et al. (2011). Vascular recovery promoted by atorvastatin and simvastatin after experimental intracerebral hemorrhage: magnetic resonance imaging and histological study. J Neurosurg, 114:1135-1142.
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